CZ321594A3 - Pharmaceutical preparation for inhibiting changes of skin and vagina - Google Patents

Abstract

A method of inhibiting atrophy of the skin or vagina comprising administering to a human in need thereof an effective amount of a compound having the formula <CHEM> wherein R<1> and R<3> are independently hydrogen, -CH3, <CHEM> wherein Ar is optionally substituted phenyl; R<2> is selected from the group consisting of pyrrolidine, hexamethyleneamino, and piperidino; or a pharmaceutically acceptable salt of solvate thereof.

Description

A pharmaceutical composition for inhibiting skin and vaginal changes

Technical field

The invention relates to a pharmaceutical composition for the inhibition of skin and vagina atrophy.

BACKGROUND OF THE INVENTION

Changes (atrophy) of the appearance and texture of skin with increasing age are proverbial and well documented both qualitatively and quantitatively. Assessment is highly subjective and greatly affects individuals. To a large extent, the effect of general skin changes with age is cosmetic, but may have pathological consequences, many of which are psychological in nature, meaning that individuals, for example, feel "old", depressed, and with loss of sexual attraction. Skin of the elderly can have pathological consequences such as the ability of the skin to heal wounds- Generally, skin changes are considered a normal and gradual consequence of the aging process and are accepted- Regardless of Acceptability of aging, there is a special period in a woman's life meriopausa when gradual aging greatly accelerates especially with regard to the vagina and skin. Often this can greatly accelerate and the severity of change can contribute to pathological and psychological fear. In addition, these changes can lead to discomfort such as itching, dryness and painful intercourse, which can lead to loss of sexual enjoyment, marital harmony and in some cases social. consequences such as divorceHow. Above mentioned, changes or aging of the skin can have both qualitative and quantitative aspects. As a qualitative aspect, smoothness and texture measurements, i.e., roughening of the view, changes in elasticity and thus affecting the mechanical properties of the skin and changes in skin pigmentation are mentioned. These qualitative changes generally lead to the above-mentioned conditions of altered skin: wrinkles, roughness, wilting, blotchy. Quantitative aging of a woman's post-menopausal skin is measured as a decrease in mitotic keratirocyte rate, changes in skin thickness, linked to the moisture content of the skin and a decrease in the excretion of hydropyrolirium in the urine, the rate of decrease in collagen reversal. Qualitative skin changes, i.e. visual and mechanical properties, are the result of quantitative changes, i.e., losses or changes in extracellular matrix components. Therefore, the beneficial effect of post-menopausal skin change therapy can be evaluated without relying on subjective analysis, although subjective improvement can. be the ultimate desirable effect.

In the case of vaginal changes, the quantitative aspect is the amount of moisture scabbard, which is controlled by the degree of secretion of the skin glands, with a qualitative consequence of feeling comfortable. • Currently, the two main therapies for treating skin changes and vagina in name-pausals are women. The first therapy is of a strictly cosmetic nature, such as the use of make-up, skin moisturizers, night creams and vaginal agents. Although this cosmetic therapy does not affect the »physiological causes of change, it often achieves a subjective, beneficial effect. The second type of therapy involves treating physiological causes with active medicinal agents, mainly vitamin A and estrogens. The efficacy of the vitamin A used is questionable and is known to have significant undesirable side effects, which limits its use. During the menopause, the levels of estrogen produced by the ovaries are rapidly reduced. This decrease in estrogen is manifested by the effect on the skin and vagina and causes a significant acceleration of the natural change process - often estrogen replacement therapy is beneficial for the treatment of skin and vaginal changes. However, this estrogen replacement therapy has undesirable side effects, usually severe, such as the possible development of cancer. The use of progestiral agents leads to undesirable psychological phenomena. The use of estrogen replacement therapy alone to treat skin and vaginal changes is not common for undesirable side effects. Therefore, effective and safe substances are sought which would be useful to positively affect physiology and thus improve the qualitative features of the skin and vaginal properties of the post-menopascular woman.

SUMMARY OF THE INVENTION

The pharmaceutical composition for inhibiting skin and vaginal changes is based on the invention. The composition of claim 1, wherein the compound of formula (I) is a 2-phenyl-3-aroylbenzothiophene derivative

where it means

R ¹ and R ³ independently of one another are hydrogen, methyl, -C = O or -C = O (C 1-6 alkyl) Ar wherein Ar is optionally a phenyl substituent, R 2 pyrrolidino, hexamethylenimino or piperidino, or a pharmaceutically acceptable salt thereof salts and solvates.

The present invention is based on the discovery that selected 2-phenyl-3-arylbenzothiophene (benzothiophenes) derivatives of Formula I are useful for inhibiting skin and vaginal changes. According to the invention, a person in need of such treatment is administered a dose of a selected 2-phenyl-3-aroy-benzothiophene derivative of formula I or a pharmaceutically acceptable salt or solvate thereof effective to inhibit skin and vaginal changes or symptoms thereof. The term inhibition herein is of generally known significance and includes prophylactic o4 sparing events which may present changes, skin and vagina or symptoms thereof, and control and / or treatment of already occurring skin and vagina changes and symptoms thereof. Pharmaceutical

The compositions of the invention are useful for both therapeutic and prophylactic treatments of Raloxiferi, a compound of the invention. formula (I) is the hydrochloride salt of a compound of formula (I) wherein R ¹ and R ^{3 are} hydrogen and R ^{2 is a} piperidiryl group and is a nuclear regulator molecule. It has been shown that raloxiferi binds to the estrogen receptor and was originally thought to be a molecule whose function and pharmacology was antiesterogenic in that it blocked the ability of estrogen to activate uterine tissue and estrogen-dependent breast cancer. estrogen activity in some cells, however, in cells of another type, raloxiferi activates some genes as estrogeri and has the same pharmacology, for example osteoporosis and hyperlipidemia. The unique profile that raloxiferi has and the difference from estrogen are now considered unique to activate and / or suppress various gene functions by the ralaxifene-estragen receptor complex as opposed to activation and / or suppressing genes by the estrogen receptor complex. Therefore, although raloxifers and estrogeres use the same receptor, the pharmacological result of gene regulation by the two agents is not easily predictable and is unique to each of them. . The positive effect of raloxifene and its selected analogues results in improved qualitative properties of the skin and vagina.

In general, the compounds are formulated with conventional excipients, diluents or carriers and compressed into tablets or formulated into elixirs or solutions for conventional oral administration or for iritramuscular or intravenous administration or for topical administration. The compounds of Formula I may also be administered transdermal and can be formulated into pharmaceutical compositions with prolonged freeing.

The 2-phenyl-3-aroybenzothiophene derivatives of formula (I) may be prepared by methods known per se or as described in detail in U.S. Pat.

418068 and 4,380,635. Generally, starting from berizo [b] thiopheria having a hydroxyl group at the 6-position and a 2- (4-hydroxyphenyl) group. A protecting group is introduced into the starting material, the compound is alkylated, and the protecting group is removed to give the compound. Formula I - Examples of methods for preparing such compounds are described in the aforementioned U.S. Patents. Substituted phenyl includes phenyl substituted by one or two substituents selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 4 alkoxy, hydroxy, nitro, chloro or fluoro, or trichloromethyl or trifluoromethyl. Derivatives 2- The phenyl-3-aroylbenzothiophene (benzothiophenes) of the formula I used according to the invention form pharmaceutically acceptable acid addition salts or bases with various inorganic and organic acids and bases, and the invention therefore also relates to physiologically acceptable salts commonly used in the pharmaceutical industry.

Examples of pharmaceutically acceptable mineral acids useful in the preparation of pharmaceutically acceptable salts include, but are not limited to, hydrochloric, hydrobromic, hydroiodic, nitric, phosphoric, phosphoric and sulfuric acids. Salts derived from organic acids such as aliphatic monocarboxylic and dicarboxylic acids may also be used. , phenyl-substituted alkanoic acids, hydroxyalkanoic and hydroxyalkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids. Such pharmaceutically acceptable salts prepared using mineral or organic acids include, for example, acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, berate. b zoate, chlorberisoate, methylbberisoate, methoxybenzoate, dini trobenzoate, hydroxybenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate, (3-hydroxybutyrate, butiri-1,4-dioate, hexiri-1,6-dioate, caprate, caprylate, chloride, cinnamate, citrate, format, fumarate, glycolate, heptarioate, hippurate, lacquer melt, malate, hydroxylate, malonate, mandelate, mesylate, nicotiriate, isonicotinate, nitrate , oxalate, phthalate, terephthalate, phosphate, monohydrogeriphosphate, dihydrogerifosphosphate, metaphosphate, pyrophosphate, ProPiolate, propionate, phenylpropionate, salicylate, sebacate, succinate, suberate, sulfate, hydrogen sulphate, pyrosulphate, sulphonate, hydrogen sulphate, hydrogen sulphate, sulphonate, sulphonate chlorobenzenesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, methisulfonate, naphthalerium-sulfonate, phthalene-2-sulfonate, p-toluenesulfonate, xylenesulfonate and tartrate. The hydrochloride salt is preferred.

The pharmaceutically acceptable acid addition salts are generally prepared by reacting a compound of formula I with an equimolar or excess amount of acid. The reactants are generally mixed in a solvent, both components such as diethyl ether or benzene. The salts generally precipitate out of solution within one hour to 10 days and can be isolated by filtration or the solvent can be stripped off by methods known per se.

Bases used for the preparation of base addition salts include, for example, ammonium hydroxide and alkali and alkaline earth metal hydroxides, carbonates and bicarbonates, as well as aliphatic and primary, secondary and tertiary amines, aliphatic diamines and hydroxyalkylamines. Particularly suitable bases for the preparation of base addition salts include ammonium hydroxide, potassium carbonate, sodium bicarbonate, calcium hydroxide, methylamine, diethylamine, ethylleridlamine, cyclohexylamine and ethariolamine. therefore, they are preferably used for the preparation of liquids or emulsions. The pharmaceutical compositions of the invention are prepared by methods known per se. For example, the compounds of Formula I may be formulated with conventional excipients, diluents, or carriers to form tablets, pills, capsules, suspensions, and powders.

Examples of suitable carriers, excipients and diluents include fillers and extenders such as starch, sugars, mannitol and silicic acid derivatives; Binders such as carboxymethylcellulose and other cellulose derivatives, alginates, gelatin and polyvinylpyrrolidone; humectants such as glycerol; dispersing agents such as calcium carbonate and sodium bicarbonate; dissolution retarding agents such as paraffin; resorption accelerating agents such as quaternary ammonium compounds; surfactants such as cetyl alcohol, glycerol morostearate; adsorptive carriers such as kaolin and beritoriite; and lubricants such as talc, calcium and magnesium stearate, and solid polyethylene glycols.

The compounds of formula (I) may also be formulated as elixirs and solutions for routine oral administration or solutions suitable for parenteral administration, for example by intramuscular, subcutarine or intravenous routes. In addition, the compounds of formula (I) are very well suited for preparing sustained release pharmaceutical compositions. active substance. The pharmaceutical compositions may also be formulated so as to release the active ingredient. Only or preferably in a certain part of the gastrointestinal tract. For some time. Coatings, coatings and protective matrices may be prepared, for example, from polymeric substances or waxes. Needed For Inhibition. changes in skin and vagina, depending on the severity of the condition, the route of administration and the like, and are determined by the physician. As a rule, the daily dose of the active ingredient is about 0.1 to about 1000 mg / day and especially about 50 to about 200 mg / day. Such a dose is administered at once or in a single dose. three daily doses or more often as needed to effectively treat or prevent skin and vaginal changes or symptoms thereof.

For topical administration, the compound of formula (I) of the present invention is formulated in a manner known per se for direct application to a particular site. Ointments, lotions, pastes, jellies, sprays and aerosols are commonly used for this purpose. The percentage by weight of the compound of the formula (I) according to the invention in such a pharmaceutical composition depends on various factors, but in general it is. 0.5 to 95%, based on the weight of the pharmaceutical composition as a whole, and is generally 1 to 25%.

The pharmaceutical compositions may be in the form of an aqueous or non-aqueous solution or dispersion, or in the form of an emulsion or suspension. Such pharmaceutically acceptable compositions may contain pharmaceutically acceptable carriers and adjuvants well known in the art. physiologically selected as an additive to water from the group consisting of acetone, ethanol, isopropanol, glycol ethers such as the trade name "Dowariol", polyglycols and polyethylene glycols, short chain alkyl esters of 1 to 4 carbon atoms in the alkyl moiety, such as, preferably, ethyl lactate or isopropyl lactate, fatty acid triglycerides such as the products of the trade name "Miglyol. isopropyl myristate, animal, mineral and vegetable oils and polysiloxanes. The pharmaceutical compositions of the invention may also contain thickeners such as cellulose and / or cellulose derivatives. They may also contain gums such as sarithan, guar gum or locust bean gum or arabic gum or may optionally contain polyethyleniglycols, bontones and seamorphites. Optionally, they may contain adjuvants selected from the group consisting of antioxidants, surfactants, other preservatives, film-forming agents, keratolytic or comedolytic agents, perfumes and dyes. They may also contain other active substances for the above or other purposes. Such antioxidants include, but are not limited to, tert-butyl hydroquinone, butylated hydroxyariisol, butylated hydroxytolueri, and α-tocopherol. and derivatives thereof Galerical forms principally adapted for topical use, may be in the form of creams, lotions, gels, dispersions or microemulsions, conductors thickened to a greater or lesser extent, impregnated pads, ointments or sticks or may be in the form of aerosols in spray form or a foam form, or may be in the form of a soap. The following Examples of pharmaceutical compositions are intended to illustrate the invention and do not limit it in any way. By an active substance is always meant a compound of formula I.

Examples

Example of Pharmaceutical Composition 1 - Gelatin Capsule

Hard gelatine capsules are prepared from the following ingredients:

Amounts (mg / capsule) active substance 0.1 to 1000 starch, NF 0 to 650 starch, flowable powder 0 to 650 silicone fluid 350 mPas 0 to 15

Said components are. they are passed through a No. 45 mesh U.S. sieve.

(sieve size 355 micrometers) and filled into hard gelatin kapslíJakožto Examples of particular pharmaceutical compositions in capsules include compositions containing active ingredient of the formula I wherein R ² is piperidino, and R1 and ^R3 are hydrogen (raloxifene). Such capsules have the following composition:

An example of a pharmaceutical composition is a 2-raloxifene capsule

Quantity (mg / capsule)

raloxifene 1.0 starch, NF 112.0 starch, melting powder 225.3 silicone fluid 350 mPas 1.7

Example of a pharmaceutical composition 3-raloxifene capsule

Quantity (mg / capsule) raloxifene 5.0 starch, NF 108.0 starch, flowable powder 225.3 silicone fluid 350 mPas 1.7

Exemplary pharmaceutical composition 4-raloxifene capsule

Amount (mg / capsule) raloxifene 10.0 starch, NF 103.0 starch, flowable powder. 225.3 silicone fluid 350 mPas 1.7

Example of Pharmaceutical Composition 5-Raloxifene Capsule

Quantity (mg / k.apsle) raloxifene 50.0 starch, NF 150.0 starch, flowable powder 397.0 silicone fluid 350 mPas 3.0

Certain compositions of such pharmaceutical compositions may be varied according to the intended use. Example of Pharmaceutical Composition 6 - Tablets

Tablets are prepared from the following ingredients:

Amount (mg / k.apsle)

active substance 0.1 to 1000 cellulose, microcrystalline 0 to 650 silicon dioxide, sublimated 0 to 650 stearic acid 0 to 15 Dec Said components are mixed and compressed by yourself acquaintances

Tablets Example of pharmaceutical composition 7 - tablets

Tablets containing in each case 0.1 to 1000 mg of an active ingredient of the formula I can also be prepared as follows: Quantity (mg / tablet) active substance 0.1 to 1000 starch 45.0 cellulose, microcrystalline 35.0 polyvinylpyrrolidone (10% solution in water) 4.0 sodium carboxymethylated starch 4,5 magnesium stearate 0.5 talc 1.0

The active ingredient, starch and cellulose are passed through a No. 45 mesh U.S. sieve. The polyvinylpyrrolidone solution was mixed with the powder obtained and passed through a No. 14 mesh U.S. sieve. (1400 micrometer mesh diameter). The granules so obtained are dried at 50 to 60 ° C and passed through a No. 18 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate and talc are passed through a No. 60 mesh U.S. sieve. (mesh diameter 250 microns), they are added to the granules, mixed and compressed into tablets Example of pharmaceutical composition 8 - suspension

A version containing in each case 0.1 to 1000 mg of active compound of the formula I per 5 ml dose is prepared as follows:

active substance 0.1 to 1000 mg sodium carboxymethylcellulose 50.00 mg syrup 1,25 mg benzoic acid solution 0, 10 ml flavoring q. in. dye q-v. purified water to 5.0 I ml

The active ingredient is passed through a No. 45 sieve. 45 raesh U.S. (mesh diameter 355 microns) and mixed with riatriumcarboxymethylcellulose and syrup to form a smooth paste. Add a solution of benzoic acid, flavoring and coloring agent, diluted with a little water, while stirring.

The active compound of the formula I is:. can: also work on the farm ^- ceutical Remedies for topical Use · Example of pharmaceutical Resource 9 Component Amount (mg / 5 ml) hydroxypropylcellulose 1.5 active substance 1.5 to 30 isopropanol qs 100.00 Example of pharmaceutical 10 Component Amount (mg / 5 ml) h ydr oxyP r opleleululsis 1, 5 ethyl lactate 15.0 active substance 1, 5 to 30 isopropanol qs 100.00 Example of pharmaceutical means 11 Component Amount (mg / 5 ml) h ydr o xy p r o pylcelulase 1.00 butylated hydroxytoluene AND 0.02 active substance 1.5 to 25 ethariol qs 100.00 Example of pharmaceutical 12 Component Amount (mg / 5 ml) hydroxypropylcellulose 1, 5 butylated hydroxytoluene 0.01 triglycerides of Cs-i2 ^m unfortunate acids 10.0 active substance 1.5 to 30

isopropanol qs

Formulations 9-12 have. gel form.

Example of a pharmaceutical composition 13

Ingredient isopropanol active substance triglycerides of C 6-1 fatty acids

Example of a pharmaceutical composition 14

Ingredient ethanol ethyl lactate active substance triglycerides C3-12 fatty acids

Example of Pharmaceutical Composition 15

Ingredient isopropanol acetone ethyl lactate active substance triglycerides of C 6-12 fatty acids

Example of Pharmaceutical Composition 16

Ingredient ethanol butylated hydroxytolueri active substance

Pharmaceutical Compositions 13, 14, 15

100.00

Amount (mg / 5 ml) 46.00

1.0 to 15 49.0

Quantity (mg / 5 ml) 46.00 10.0

1.5 to 20 30.0

Quantity (mg / 5 ml) 47.00 10.00 10.0

1.0 to 15 30.0

Amount (mg / 5 mL) 95.08

0.02

1.5 to 25 and 16 are in the form of watermarks.

Example of Pharmaceutical Composition 17

Ingredient white vaseliria liquid paraffin refined paraffin wax. active substance

Amount (mg / 5 ml)

50.0

15.0

32.0

1.0 to 20

Example of a pharmaceutical composition 18 Ingredient white vaseliria liquid Paraffin refined paraffin wax active substance

Amount (mg / 5 ml)

50.0

13.0

32.0

1.0 to 20

The pharmaceutical compositions 17 and 18 are in the form of sticks.

Tests of pharmaceutical composition

T est 1

Change skin

For the clinical study, 3 to 20 post-name women in good health are selected. These women are selected for some signs of rapid skin changes, such as a rapid increase in the number of wrinkles on the face or chicken footprints, rapid skin pigmentation with age spots or other signs of rapid skin aging. It is recalled that these changes are highly subjective and must therefore be taken into account when choosing women. Skin changes may also have other reasons, for example, due to adverse effects of ultraviolet rays after sunbathing or other adverse environmental effects, and are therefore excluded from the group.

The first component of the study is qualitative and subjective, which is the assessment of improving the appearance of women. Such assessment requires an Initial Appraisal Appearance for future comparison. Such an initial assessment may take the form of standardized queries such as. woman evaluates her appearance, photo, or psychological profile. The second component of the test is quantitative. This quantitative assessment includes measurement of urinary excretion of hydroxy Proline, moisture content of the skin, glycosaminoglycans in the skin, and changes in skin elasticity and suppleness. Methods for assessing these factors are described in The Menopause, edited by R.J. Beard, Univewrsity Press, Chapter 7 (1977) and in Methods in Skin Research, D. Skerrow and C.J. Skerrow, John Wiley & Sons Ltd, Chapter 22, Arialysis of Sebaceous Lipids, pp. 587-608, 1985. Initial Assessment First Performed Initial Assessment The women selected for the initial assessment are administered orally 40 up to 400 mg of active ingredient deriria at once or in several units. Or the active substance is administered to women topically to the skin areas most affected by the changes. For this purpose, a suitable pharmaceutical composition containing 5 to 50% by weight of the active compound of the formula I according to the invention is used at designated sites once or twice daily. Each of these therapies lasts for 2 to 12 months. Then qualitative and quantitative evaluations are carried out at appropriate intervals.

A positive result is an improvement in the overall quality index of the female appearance and / or improvement in qualitative parameters, such as an increase in urinary excretion of hydroxyproline, an increase in collagen production, an increase in moisture content of glycosaminoglycans, suppleness or skin elasticity.

Test 2

Changing the vagina

For the clinical study, 3 to 20 with vaginal changes due to post-raenopause are selected. • Women are otherwise in good health. These women are asked daily for vaginal itchiness and sexual comfort. Clinical treatment of these women is similar to research into skin changes. In particular, the use of vaginal suppositories containing 5 to 25% of an active ingredient according to the invention of formula (I) is particularly emphasized. The usefulness of the compound of formula (I) is evidenced by the positive effect of comfort and sexual intercourse and / or vaginal pruritus. The usefulness of the compound of the formula I according to the invention has been shown in both of the above tests.

Industrial applicability

Pharmaceutical composition for the inhibition of skin changes and vagina containing, as active ingredient, a 2-phenyl-3-aroylbenzothiophene derivative or a pharmaceutically acceptable salt or solvate thereof17

Claims (7)

What is claimed is: 1. A pharmaceutical composition for the inhibition of skin and vagina alteration comprising as active ingredient a 2-phenyl-3-aroylbenzothiophene derivative of the formula I ÍAIO! \ 'I $ γη QYofi IX 6 OISOQ where it means R ¹ and R ³ are independently hydrogen, methyl, a group -C = 0 or -C = 0 (Ci-6alkyl) Ar where Ar is optionally substituted phenyl, R ² yne pyrrolidino, hexamethyleneimino, and piperidino; or a pharmaceutically acceptable salts or solvates. Pharmaceutical composition for the inhibition of skin and vaginal changes according to claim 1, characterized in that it comprises, as active ingredient, a 2-phenyl-3-aroylbenzothiophene derivative of the general formula I, wherein the individual symbols are as defined in claim 1 in the form of the hydrochloride salt. Pharmaceutical composition for the prophylactic inhibition of skin and vaginal changes according to claim 1, characterized in that it comprises, as active ingredient, a 2-phenyl-3-aroy-1-benzothiophene derivative of the formula I, wherein the individual symbols are as defined in claim 1. 4. A pharmaceutical composition according to claim 1, wherein the active ingredient is a 2-phenyl-3-aroylbenzothiophene derivative of formula (I) which is a compound of formula (I) or a hydrochloride salt thereof. 5. A composition according to claim 1, wherein the active ingredient is a 2-phenyl-3-aroylbenzothiophene derivative of the formula I wherein: R @ ¹ and R @ ³ independently of one another are a hydrogen atom, a methyl group, a group -C = 0 or -C = O; (Ar 1-6 alkyl) Ar wherein Ar is optionally substituted phenyl, R ² pyrrolidino, hexamethyleneimino or piperidino, or pharmaceutically acceptable salts or solvates thereof. 6. A composition according to claim 5, wherein the active ingredient is a 2-phenyl-3-aroylbenzothiophene derivative of the formula I, wherein the individual symbols are as defined in claim 1 in the form of the hydrochloride salt. Pharmaceutical composition for the prophylactic inhibition of vaginal changes according to claim 5, characterized in that. The compound of claim 1, wherein the active ingredient is a 2-phenyl-3-aroylbenzothiophene derivative of the formula I, wherein the individual symbols are as defined in claim 1. Pharmaceutical composition for the inhibition of vaginal changes according to claim 5, characterized in that it contains, as active ingredient, a 2-phenyl-3-aroy-benzothiophene derivative of the formula I which is a compound of the formula or a hydrochloride salt thereof.